Activation of mesangial cell signaling cascades in response to mechanical strain.

Abstract

Mesangial cells (MCs) are constantly exposed to pulsatile stretch and relaxation in their role as architectural support for the glomerulus. There is no cell proliferation in normal glomeruli. In contrast, animal models of increased glomerular capillary pressure are characterized by resident glomerular cell proliferation and elaboration of extracellular matrix (ECM) protein, resulting in glomerulosclerosis. This process can be ameliorated by maneuvers, such as angiotensin converting enzyme inhibition, that reduce glomerular capillary pressure. MCs grown on ECM-coated plates and exposed to cyclic stretch/relaxation proliferate and produce ECM protein, suggesting that this may be a useful in vitro model for MC behavior in response to increased physical forces. Previous work has shown induction of c-fos in response to application of mechanical strain to MCs, which may induce increases in AP-1 transcription factor activity, which, in turn, may augment ECM protein and transforming growth factor beta transcription and cell proliferation. Stimuli that lead to c-fos induction pass through mitogen-activated protein kinase (MAPK) pathways. Three MAPK cascades have been characterized in mammalian cells--p44/42 (classic MAPK), the stress-activated protein kinase/Jun terminal kinase (SAPK/JNK) pathway, and p38/HOG--and mechanical strain activates p44/42 and SAPK/JNK in cardiac fibroblasts. However, in contrast to MCs, these cells do not proliferate in response to physical force. Accordingly, we studied activation of the MAPK pathways in MCs exposed to mechanical strain.